For subscription, donation and editorial information and to read our Statement of Purpose, visit Aids Treatment News' page here at The Body.

CMV, RS-79070:Community Concern As MajorDrug's
Development Suspended

by John S. James

Last week AIDS treatment activists learned that plans for
future Phase III trials of RS-79070, an oral prodrug of
ganciclovir, had been suspended by Hoffmann-La Roche,
apparently due to concern that there are no longer enough new
cases of CMV retinitis to justify the expense of continuing
development. A smaller phase II trial, which is still
recruiting, will continue (see announcement below). The
decision was made at Roche offices in Basel.

RS-79070 is a chemical relative of ganciclovir which can be
readily absorbed orally, and then is changed to ganciclovir
in the bloodstream. It provides much higher blood levels of
ganciclovir than the currently approved oral drug, which is
poorly absorbed. Because of its lower efficacy, the oral
ganciclovir which is now available cannot be used for
induction (the initial high-dose treatment of CMV retinitis),
and is controversial for maintenance (long-term treatment of
active CMV disease after induction) and prophylaxis
(prevention of CMV disease in persons who are at risk).

Advertisement

RS-79070 may replace intravenous treatments or ocular
implants for CMV disease, with a pill which is taken once a
day (twice a day for the first three weeks of treatment for
the induction phase). Because it delivers ganciclovir to the
body, it will have the same basic side effects of that drug.
Unfortunately, current drug-development rules require large
and expensive phase III trials before RS-79070 can be
marketed -- even though (1) this drug serves only as a better
delivery vehicle for supplying ganciclovir orally, (2) a less
effective oral ganciclovir is already approved, and (3) the
smaller phase II trial now recruiting will show whether or
not RS-79070 is comparable to intravenous ganciclovir for
induction treatment of CMV retinitis.

Project Inform, in San Francisco, which first learned of the
decision to suspend development of the large trials required
for marketing, is deeply concerned because it has been
hearing quite good anecdotal reports about RS-79070 from
physicians and patients -- and also because of reports that
the number of new cases of CMV retinitis may be starting to
rise again, due to more treatment failures after longer-term
use of the new combination anti-HIV regimens. GMHC (Gay Men's
Health Crisis, in New York) is organizing a letter of protest
to Roche.

The phase II trial described below will continue -- and will
provide data which might justify reviving the plans for phase
III trials which could lead to general availability of RS-
79070.

CMV Retinitis,Newly Diagnosed: RS-79070 Trial

Persons with newly diagnosed CMV retinitis may be eligible
for this trial which compares RS-79070 with currently
approved intravenous ganciclovir for CMV retinitis. After
four weeks for the randomized comparison, volunteers in
either group will be allowed to continue treatment with open-
label RS-79070.

For the first three weeks (induction phase), both groups will
receive treatment twice a day -- either with 5 mg/kg of
intravenous ganciclovir, or 900 mg orally of RS-79070. After
the induction, each group will receive the same treatment
only once per day (maintenance phase). After one week on the
maintenance dose, the blinded study will be over, and
volunteers can continue treatment with RS-79070, the oral
prodrug.

This trial has not been well known and so far has recruited
only 13 of the total of 60 to 70 volunteers it needs -- which
may have helped precipitate the decision to suspend
development of the large phase III trials.

For contact information for a site in your city, call the
AIDS Clinical Trials Information Service, 800/TRIALS-A.
(Note: As of May 1, this trial was not yet in the regular
database at ACTIS, but the contact information was available
in card file there. Also as of May 1, a Los Angeles site is
possible but not yet official.)

FDA Community MeetingMay 16: Clinical Trialsand
Viral Load

On April 28 the FDA announced a public meeting to discuss
possible use of viral load instead of "clinical endpoints"
(usually death or the development of an AIDS-defining
illness) in certain clinical trials of antiretrovirals.
Persons can also submit a position paper or list of
questions, in advance of the meeting.

The meeting will be held on Friday, May 16, from 1:00 to 4:00
in Conference Room G of the Parklawn Conference Center,
located on the third floor of the Parklawn Building, 5600
Fishers Lane, Rockville, Maryland. The building is wheelchair
accessible, and can be reached by the Washington D.C. Metro.
Because of security measures, persons should allow at least
15 minutes extra time for arriving. You will need a photo ID
to enter the building.

A written position paper may be submitted before the meeting
to Richard Klein, HIV/AIDS Program, Office of Special Health
Issues, HF-12, 5600 Fishers Lane, Rockville, MD 20857, or by
fax to 301/443-4555.

If you have questions about the meeting, you can call Richard
Klein at 301/827-4460, or send email to
Rklein@bangate.fda.gov.

Comment

This community forum concerns a mid-July meeting of the
Antiviral Drugs Advisory Committee -- not yet officially
announced -- which will examine possible changes to
regulations to allow sustained reductions in viral load to
substitute for "clinical endpoints" (deaths or serious
disease progression) now required for proof of antiretroviral
drug efficacy in confirmatory clinical trials. It is widely
believed that the FDA wants to make this change, and will do
so after the July Advisory Committee meetings.

Under current "Accelerated Approval" regulations,
antiretrovirals can be approved for marketing based on viral
load reductions and similar evidence that they work. But the
drugs approved this way must then go through large, long-
lasting clinical-endpoint trials to prove that the viral load
and other blood-test improvements translate to real benefit
to patients. Due to advances in recent years in the
understanding of HIV disease, these trials have become
increasingly ethically problematic, and are seen by many as a
huge misdirection of resources -- money, trained
professionals, and not least, the trial volunteers -- which
should be focused instead on more practical trials which seek
answers which physicians need today.

Note: For an in-depth look at the rapidly changing thinking
about AIDS clinical trials, see two articles in the current
issue of SCIENCE (volume 276, April 25, 1997) -- "AIDS Trials
Ethics Questioned," by Jon Cohen, pages 520-523 and "Current
Problems and the Future of Antiretroviral Drug Trials," pages
548-550, by Dr. Joep M.A. Lange.

Sam Avrett is Associate Scientific Director of the International AIDS Vaccine Initiative (IAVI), a new organization encouraging the development of safe and effective vaccines for use throughout the world. Last year, Sam co-founded the AIDS Vaccine Advocacy Coalition (AVAC); he has worked with HIV prevention programs in New York City and
Washington D.C., and he served with the Peace Corps in theCentral African Republic.

This interview was completed before the recent report --
published this week in NATURE MEDICINE -- about protecting
two chimpanzees from HIV infection with a DNA vaccine.

AIDS Treatment News: Aside from idealism or public service,
why should someone who already has HIV be interested in
research to develop a preventive vaccine for uninfected
people?

Sam Avrett: I think that most HIV-infected people are
concerned about ending this epidemic. Vaccine research is
critical because a vaccine is one of the best foreseeable
ways to control the AIDS epidemic, both in the U.S. and
around the world. Anyone who has worked in HIV prevention
knows that, while behavioral change and condoms and clean
needles go a long way toward preventing HIV, staying
uninfected is hard. In the United States, studies have shown
that in high-risk populations, like sexually active gay men,
more than two in a hundred are newly infected each year, even
with the best possible counseling. Although behavior change
can do a lot, it is just not realistic to expect individual
behavior change, by itself, to control this epidemic.

In terms of how basic research for a vaccine might benefit
both infected and uninfected people, one possible step in
developing an effective AIDS vaccine may be understanding the
"correlates of immunity" -- in other words, what immune
responses actually protect against the virus. If we knew
this, we might be able to develop immune-based therapies for
those already infected.

The body already controls HIV effectively for some time after
infection, usually several years or more. We might be able to
maintain this response indefinitely if we knew more about how
it worked and how it was lost.

ATN: What is the status of AIDS vaccine research now?

Avrett: There are about a dozen vaccines being tested in
animal studies, or small human safety studies, but none have
been tested for effectiveness in large clinical trials. These
include "whole-killed" and "live-attenuated" vaccine designs
that have worked against measles, mumps, and typhoid;
"subunit" or "peptide" vaccines made from parts of HIV
proteins; "recombinant vector" vaccines that use harmless
viruses to "show" HIV proteins to the immune system; and DNA
vaccines, which also "show" HIV proteins to elicit an immune
response.

The problem is that all of this needs more research and more
funding. Researchers need better starting viruses, better
animal models and immune system cells that can replicate what
happens in real infection, and larger studies for conclusive
results with clinical, rather than laboratory, endpoints.

ATN: What funding is now available for vaccine research and
development?

Avrett: It can cost about $100 million over ten years to
research and develop the average vaccine. The U.S. National
Institutes of Health will spend about $150 million of its
nearly $1.5 billion HIV research budget next year on AIDS
vaccine research, mostly in basic science and in clinical
trial preparation. The Department of Defense has budgeted
about $20 million for applied research on HIV vaccines.
Pharmaceutical and biotechnology companies, including Merck,
Pasteur-Merieux Connaught, or Chiron, might be spending a
total of $20 million or more, but no one really knows.

Is this enough? There is lots of research that is not
happening because of funding. The cost of treatment and care
for the 900,000 people living with HIV in the United States,
let alone the 40 million people living with HIV worldwide, is
astronomical. Just compared to the cost of treatment and care
for the people who will otherwise become infected -- more
than three million new infections every year worldwide -- the
benefits of a vaccine would far outweigh the costs.

ATN: Aside from advocating for more money for research, what
can the community do?

Avrett: At its best, community involvement also helps
researchers with informed, honest, and impartial advice.
Community advocates can support funding of research, and can
provide researchers with input on research priorities,
research quality, feasibility of research studies, and
community education needs.

ATN: What is IAVI's role in this?

Avrett: IAVI, the International AIDS Vaccine Initiative, was
started last year after several international meetings of
researchers, policy experts, financial experts, and members
of the HIV-affected communities identified the need for new
strategies and new ways of approaching HIV vaccine
development. IAVI's strategies include direct funding of
others to fill important gaps in applied research and vaccine
development, advocacy for international vaccine development,
and collaboration with governments, funders, regulatory
agencies, and private industry to encourage greater
investment into HIV vaccine research and development. IAVI
can complement the efforts of the NIH, UNAIDS, pharmaceutical
companies, and other organizations, to ensure the development
of safe, effective HIV vaccines that can be used throughout
the world.

ATN: How can our readers find out more and become involved?

Avrett: First, learn more about the issue. For important
background information on the current state of vaccine
sciences, see the IAVI REPORT, the newsletter of the
International AIDS Vaccine Initiative. You can obtain copies
from IAVI; phone 212/852-8326, fax 212/852-8279, or mail a
request to IAVI, c/o The Rockefeller Foundation, 420 Fifth
Avenue, New York, NY 10018, or send email to
103423.355@compuserve.com.

You could call the AIDS Vaccine Advocacy Coalition, 415/248-
1330, or check the VACT UP Web site for vaccine advocates, at
http://www.vactup.org.

Also, you might be able to work with existing AIDS advocacy
or service organizations to get them interested in paying
attention to the need for an HIV vaccine. And it certainly
would help to let your representatives in Congress hear from
you, and know that you want more funding for research on HIV
treatments and vaccines.

And if you live in a city with an HIV vaccine trial site
[Baltimore, Birmingham, Boston, Chicago, Denver, Nashville,
New York, Philadelphia, St. Louis, San Francisco, or
Seattle], you can join the site's Community Advisory Board.
Contact information for each city is on the VACT UP Web site,
or can be obtained from IAVI at the phone, mailing address,
or email above.

Note: Background on IAVI

"The International AIDS Vaccine Initiative, a not-for-profit
organization, was formed in 1996 after several international
consultations of researchers, policy experts, financial
experts, and members of HIV-affected communities identified
the need for new strategies and new ways of thinking about
HIV vaccine development. IAVI's mission is to ensure
development of safe, effective, preventive HIV vaccines for
use throughout the world.

"IAVI strategies to achieve this mission include: 1)
advocating for greater involvement of worldwide public and
private sectors, 2) working with governments, funders,
regulatory authorities, and private industry to create a more
favorable environment for increased investment in
international vaccine research and development, and 3)
directly funding a highly targeted, applied research and
development effort to fund others to fill gaps in existing
efforts and move new vaccine products into international
clinical trials. IAVI's current and future research
strategies are designed to accelerate evaluation of multiple
promising candidate vaccines for eventual use by populations
most in need."

1st National AIDSMalignancy Conference --Online
SummariesAvailable from April 28-30 Meeting

Extensive summaries of each day of the 1st National AIDS
Malignancy Conference were written by teams of AIDS
researchers and writers, who worked late into the night and
made their reports available everywhere by the next day,
through the World Wide Web. For U.S. medical professionals,
continuing medical education credit is available online.

We have not had time to review this material, which consists
of about 60 single-spaced pages including abstracts and
tables, and became available as this issue went to press.
Instead we will list the titles of the summary articles, so
that those interested can obtain the summaries for
themselves.

Note: The titles below are those of the summaries, not of the
scientific papers presented at the conference. The titles and
abstracts of the scientific presentations are also available
at the World Wide Web address below. There are 172 abstracts
online, and they are searchable by author or keyword, or can
be scanned by title. Usually each of the summaries listed
below reviews several related presentations.

AIDS-Associated Non-Hodgkin's Lymphoma: Prognostic Factors,
Survival Rates, and the Effect of Its Treatment on HIV.

Day 3

Clinical Aspects of AIDS-Related Lymphoma.

EBV: How the Kissing Virus Becomes Deadly.

AIDS-KS: Treatment Issues.

Treatment of Non-Hodgkin's Lymphoma in HIV-Positive Children:
Cause for Hope.

These summary articles (and the abstracts of the scientific
presentations themselves) are available at
http://www.healthcg.com/NCIconference.

Medicaid -- AIDS Impactof Proposed Cuts

On April 29 the San Francisco AIDS Foundation issued an
action alert asking people to call their Congressional
representatives, and members of the House and Senate budget
committees, to oppose cutting Medicaid funding, and oppose
"per capita caps" on Medicaid (which would limit Federal
reimbursement to states to a flat rate for providing medical
care for poor people with disabilities, regardless of
individual differences in the cost of their care).

On May 1, the AIDS Action Council in Washington sent a
separate alert on this issue.

The following is from the San Francisco AIDS Foundation:

"* Medicaid is the single most important program serving
people with HIV. Seven of ten dollars spent on AIDS care come
from Medicaid [Medi-Cal in California]. Medicaid provide
health care to more than 90% of children living with HIV and
roughly half of adults with AIDS.

"* Cutting Medicaid is not necessary. The Congressional
Budget Office (CBO) has forecast, as of January 1997, that
future Medicaid spending has fallen to $618 billion over the
1998-2002 period. This is below Republican proposals in 1996
for $626 billion in Medicaid spending over the same period as
part of their balanced budget proposal. It is also far below
projected Medicaid spending in the President's initial budget
proposal of December 1995.

"* Per capita caps will squeeze Medicaid AIDS care. People
living with HIV comprise less than 1% of all Medicaid
beneficiaries and their health care expenses make up only 2%
of total Medicaid costs. Nonetheless per capita caps which
are based on paying state Medicaid programs on the basis of
average costs for all people with disabilities would unfairly
target people with AIDS and others with extensive health care
needs. The average cost of care for a person with a
disability in Medicaid is approximately $8,000/year. Without
protease inhibitors or other new drugs, the average cost of
care for a persons with AIDS exceeds $20,000/year in many
locations. If states are reimbursed from the federal
government on the basis of only the initial $8,000, then
state Medicaid programs would seek ways to limit Medicaid
eligibility for people with HIV/AIDS and they would seek ways
to limit necessary health care services to people with
HIV/AIDS in the program. ..."

"Negotiations between the President and Congress over a
balanced budget agreement continue. It is possible that a
deal could be struck in the next few days and it is also
possible that they could fail to reach a deal at all. Cutting
Medicaid is not necessary to balance the budget. The HIV
community needs to weigh in forcefully at this time to let
Congress know that cutting Medicaid would limit access to
care for people living with HIV. Further cuts to Medicaid are
unacceptable.

"The San Francisco AIDS Foundation opposes the President's
proposal to cut $22 billion from Medicaid (over 1998-2002)
and his plan to institute per capita caps ... While the
President has also proposed $13 billion in new Medicaid
spending, which we support, to help mitigate harmful effects
of the welfare reform legislation that he signed, they need
not come at the expense of current Medicaid beneficiaries.

"Some Republicans in Congress are countering the President's
offer by proposing to accept the President's $22 billion in
cuts, but without his new spending proposals. Consumers need
to provide a countervailing voice in Congress to the
President's and Republican calls for harmful changes to
Medicaid."

Medical Marijuana:Questions Raisedon San
Francisco Raid

by Bruce Mirken

San Francisco District Attorney Terence Hallinan has
questioned the federal government's claim that an April raid
on a San Francisco medical marijuana buyers' club was a
routine enforcement action.

Early in the morning of April 21 Federal Drug Enforcement
Administration agents raided Flower Therapy, breaking down
the door, seizing approximately 300 marijuana plants along
with other equipment and supplies and leaving a federal
search warrant for employees to find when they arrived later
to open the club. In statements to the press, DEA officials
repeatedly characterized the raid as a routine enforcement
action against a "large-scale growing operation" and insisted
they had not singled out organizations connected to
California's Proposition 215, which legalized marijuana use
for medicinal purposes.

But the San Francisco District Attorney's office said the
raid was highly unusual. "Normally it's the duty of the
D.A.'s office to enforce the laws within the city," explained
spokesman John Shanley. Federal drug agencies, he said,
generally let local law enforcement handle the vast majority
of drug cases, involving themselves only with truly massive
operations, involving "tonnage, not pounds" of marijuana.
"What they ended up confiscating [from Flower Therapy] was
about 2 1/2 pounds, which does not warrant federal agents
being involved." Hallinan's office was not even notified that
the raid was going to occur.

Asked if the DEA had raided any other San Francisco marijuana
distributors of similar size, Shanley said, "No, which is
what makes it unusual."

On April 22 Hallinan publicly urged U.S. Attorney Michael
Yamaguchi not to prosecute individuals who might be arrested
in the raid's aftermath and took the unusual step of offering
to testify for the defense should charges be filed. "I would
testify to the fact that this group was trying to comply with
the law in the state of California," he told the SAN
FRANCISCO EXAMINER.

The San Francisco police, District Attorney's office, and
health department have been working closely with medical
marijuana buyers' clubs to develop protocols for the orderly
implementation of Proposition 215, and Shanley said that
Flower Therapy has been completely cooperative in that
process. "Why would you want to punish someone who's played
by the rules?" he asked. "This was clearly ordered by someone
who opposed Proposition 215."

DEA spokesman Stan Vegar refused to respond directly to
Shanley's and Hallinan's statements, but insisted the raid
was "absolutely not" a response to Proposition 215. The
measure "does not change our fundamental mission to enforce
the drug laws," he said. "315 plants in a complex system with
lights and hydroponics is a large-scale growing operation." A
spokesperson for the San Francisco U.S. Attorney's office
refused any comment on the case.

Meanwhile, a bill to require harsh penalties for doctors who
recommend marijuana has been introduced in Congress. S40,
introduced by Senator Lauch Faircloth (R-NC) would mandate an
eight year prison term for doctors who recommend marijuana,
as well as revocation of their DEA registration. Drug policy
reform advocates say it is too early to assess the measure's
chances of passage, but Eric Sterling, president of the
Criminal Justice Policy Foundation, said that the mood in
Congress is not encouraging. "There is a profound disconnect
between the West Coast's view of this issue and
Washington's," he said.

[Note: On April 30 a Federal judge issued a preliminary
injunction preventing the Federal government from punishing
California physicians who recommend medical marijuana to
their patients under the provisions of Proposition 215. This
injunction extends the temporary restraining order reported
in our previous issue, AIDS Treatment News #269. Judge Fern
Smith issued a 43-page ruling with the April 30 injunction.
For more information about the rights of Californians under
Proposition 215, a brochure is available from Americans for
Medical Rights, 1-888-YES-4-215. JSJ.]

Copyright 1997 by John S. James. Permission granted for
noncommercial reproduction, provided that our address
and phone number are included if more than short
quotations are used.

The Body is a service of Remedy Health Media, LLC, 750 3rd Avenue, 6th Floor, New York, NY 10017. The Body and its logos are trademarks of Remedy Health Media, LLC, and its subsidiaries, which owns the copyright of The Body's homepage, topic pages, page designs and HTML code. General Disclaimer: The Body is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through The Body should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, consult your health care provider.